Previous studies have demonstrated that activation of the RAR results in antimicrobial activity against intracellular Mycobacterium tuberculosis. Our preliminary suggest that this antimicrobial activity could be mediated through activation of the vitamin D metabolic system. In addition our data indicate that concurrent TLR and RAR activation results in amplification of both macrophage differentiation and increase in the antimicrobial response. These data suggest an important role of RAR in the innate immune response and is suggestive of a potential mechanism by which vitamin A deficiency is correlated to increase susceptibility to disease in humans. The data generated from this study should provide new avenues of research into the host defense mechanisms against M. tuberculosis, as well as potential therapeutic targets. This application is submitted by Dr. Philip T. Liu, an investigator in the field of immunology whose objective is to transition into an independent researcher. As part of his career development, he will receive training in translational immunology and molecular endocrinology through co-mentorship by Dr. Robert L. Modlin and Dr. John S. Adams. Also, Dr. Genhong Cheng and Dr. Martin Hewison will provide additional mentorship in their respective fields of expertise. This proposal also outlines the course work through the K30 program at UCLA that will help Dr. Liu increase his knowledge base and improve his ability to execute translational clinical research. In the interim Dr. Liu will be provided research space and resources with Dr. Modlin's laboratory at the University of California at Los Angeles where Dr. Liu will have all the necessary resources to successfully complete his training. In summary, this application will serve not only to address immediate and long term scientific questions, but also the career development of Dr. Liu into a successful independent researcher. Relevance to Public Health: This research proposal is of interest to public health because it is designed to investigate how the human immune system combats tuberculosis, which currently ranks as the number one infectious disease in the world. Approximately one third of the world's population is infected, and recent increase in multidrug resistant strains of Mycobacterium tuberculosis, the causative agent of tuberculosis, has underscored the need for research into defense against the bacterium. By understanding the factors that regulate the immune response to this bacterium, we can design better therapies to treat this disease.